The purpose of this proposal is to provide support for Lori Styles MD to expand her clinical research investigations and enhance her mentorship of new clinical investigators. Dr. Styles is presently an active clinical investigator with NIH and FDA funding supporting patient-oriented research in acute lung injury and cerebrovascular disease in sickle cell disease (SCD). This proposal outlines a formal research project and a plan for mentoring. The unique environment of Children's Hospital and Research Center at Oakland provides an ideal setting to accomplish these goals both through providing a large patient base and through laboratory expertise. The research plan outlined in this application describes a new clinical investigation of the use of arginine as a prophylactic treatment to prevent or reduce vaso-occlusive events in SCD. This project stems from results from an ongoing clinical trial of arginine in acute chest syndrome which has documented that treatment with arginine increases nitric oxide production and improves endothelial dysfunction in these patients. The specific aims of this research plan are 1) To comprehensively assess the physiological effects (both beneficial and deleterious) of the long term administration of oral arginine in patients with SCD and 2) To evaluate the effect of daily oral arginine on clinical vaso-occlusive events in SCD patients. Successful completion of the clinical trial and the accompanying in vitro investigations outlined in this proposal will substantially increase our knowledge about the efficacy of oral arginine as a therapy for SCD and could lead to a promising new therapy for these patients. Despite a busy clinical research career, Dr. Styles has successfully mentored several new clinical investigators on their way to an independent career. This application outlines her plans to continue and expand her mentorship role with new investigators. Dr. Styles also plans to develop a new clinical fellowship program which will focus on training new investigators specifically for clinical research in SCD.